A series of compounds of 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2,4-dione or its analogues were disclosed in United States Patent Application 20060041000. These compounds were designed to be used as inhibitors of macrophage elastase. All these compounds are hydantoin derivatives and tested in vitro for their use as matrix metalloproteinase (MMP) inhibitors.
As shown in the United States Patent Application 20060041000, all compounds tested show desirable activity and favorable selectivity profile. IC50s on MMP-12 fall in the range of 1-300 nM, therefore they are all considered to be active. Most of the above compounds do not show inhibition on MMP-1 and MMP-7 at 10 uM. Their selectivity for MMP-12 over MMP-2, MMP-3, MMP-9 and MMP-13 range from 50 to 1000 fold. These compounds seem to possess some potentials to be used in the treatment of diseases or conditions mediated by MMP-12, such as asthma, chronic obstructive pulmonary diseases (COPD), arthritis, cancer, heart disease and nephritis. However, except for the IC50 data for limited MMPs, there were no further biological data provided in detail. In addition, except the NMR and MS data, no other physical and chemical property data were provided.
Therefore, it would be desirable to understand the characteristics of these compounds and develop suitable formulations to use 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2,4-dione or its analogues for potential treatment of various diseases through inhibition of MMP.
According to the teaching of the United States Patent Application 20060041000, MMP Inhibitory Assays were conducted in aqueous buffer (50 mM Hepes, 10 mM CaCl2), 0.05% Brij 35, pH 7.5), indicating that these compounds should be fairly water soluble. However, it was unexpectedly discovered that these compounds have very low aqueous solubility. 5-[3-(4-benzyloxyphenylthio)-fur-2-yl]-imidazolidin-2,4-dione and its analogues not only exhibit a low solubility in water, but also in an acidic environment. Consequently, when administered orally in a conventional solid dosage form, a low bioavailability may be expected.
Therefore, there remains a need for developing formulations of these compounds, such as formulations that render these compounds suitable for non-invasive such as oral, intranasal and/or sublingual administrations.